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Polygenic risk for schizophrenia is associated with white matter microstructure and behavior

Poster No:

1772

Submission Type:

Abstract Submission

Authors:

Qian Qian¹, Jiayuan Xu², Chunshui Yu¹

Institutions:

¹Tianjin Medical University, Tianjin, Tianjin, ²Tianjin Medical University General Hospital, Tianjin, Tianjin

First Author:

Qian Qian
Tianjin Medical University
Tianjin, Tianjin

Co-Author(s):

Jiayuan Xu
Tianjin Medical University General Hospital
Tianjin, Tianjin

Chunshui Yu
Tianjin Medical University
Tianjin, Tianjin

Introduction:

Patients with schizophrenia have shown extensive structural, functional, and connectivity impairments compared to healthy controls. In addition to classical symptoms, patients with schizophrenia also demonstrate other cognitive and mental impairments, such as the decline in memory, attention, and execution as well as the symptoms of anxiety and depression. Furthermore, a large portion of these brain and behavioral impairments are observed in offsprings of parents with schizophrenia, indicating that genetic risk for schizophrenia may at least partially contribute to these impairments. Schizophrenia is highly heritable and polygenic risk score for schizophrenia has been associated with brain and behavioral changes in healthy populations. However, the precise effects of schizophrenia polygenic risk score on proximal white matter microstructure and then distal behavioral changes remain unknown.

Methods:

We used the UKB-released schizophrenia polygenic risk score data constructed by the standard pipeline, 384 image-derived phenotypes using using tract-based spatial statistics , 6 cognitive function tests and 8 mental health symptoms. We investigated the schizophrenia polygenic risk score effects on eight white matter microstructure measures of 48 tracts and 14 cognitive and mental health traits in up to 30,0000 adults from the UK Biobank, and further investigated the modulation of sex and index of multiple deprivation on these associations and the mediation of brain white matter phenotypes for the associations between schizophrenia polygenic risk score and behavioral outcomes.

Results:

There were 61 significant assocoations between schizophrenia polygenic risk score and brain white matter microstructure, and 11 significant associations between schizophrenia polygenic risk score and behavioral traits. We found that higher schizophrenia polygenic risk score was associated with poorer white matter integrity in many tracts, such as fornix, bilateral superior corona radiata and cingulum cingulate gyrus. We also found that higher schizophrenia polygenic risk score was associated with worse cognitive performance and poorer mental health, such as fluid intelligence, reaction time, symbol-digit substitution and mental distress. We further found that sex and index of multiple deprivation could modulate these associations. There were 81 significant causal mediation results between schizophrenia polygenic risk score, brain white matter microstructure and behavioral changes. Causal mediation analyses revealed that white matter integrity damage partially mediated the adverse effects of schizophrenia polygenic risk score on cognitive and mental health.

·Associations of schizophrenia polygenic risk score with brain white matter phenotypes.

·Causal mediation results.

Conclusions:

In this study, we aimed at clarifying these issues by (1) training the schizophrenia polygenic risk score model using three external genome-wide association studys (97,456 cases and 334,331 controls); (2) investigating the schizophrenia polygenic risk score effects on eight diffusion MRI metrics of 48 white matter tracts (N = 23,468) and 14 cognitive and mental health traits (Nmax = 299,846) in adults from the UK Biobank; (3) testing the mediation of white matter phenotypes for the associations between schizophrenia polygenic risk score and behavioral outcomes; and (4) testing the differences in the effects of schizophrenia polygenic risk score on white matter microstructure and behavioral outcomes between male and female as well as between participants with higher and lower index of multiple deprivation. These findings may improve our understanding of how schizophrenia polygenic risk score affects brain and behavior in healthy populations and indicate that genetic risk for schizophrenia may influence white matter microstructure, cognitive and mental health before the onset of this disorder.

Disorders of the Nervous System:

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ²

Genetics:

Genetic Association Studies

Higher Cognitive Functions:

Higher Cognitive Functions Other

Neuroanatomy, Physiology, Metabolism and Neurotransmission:

White Matter Anatomy, Fiber Pathways and Connectivity ¹

Novel Imaging Acquisition Methods:

Diffusion MRI

Keywords:

Cognition

Psychiatric Disorders

Schizophrenia

White Matter

Other - mental health

^1|2Indicates the priority used for review

Abstract Information

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Please indicate below if your study was a "resting state" or "task-activation” study.

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Healthy subjects only or patients (note that patient studies may also involve healthy subjects):

Healthy subjects

Was this research conducted in the United States?

Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.

Yes

Were any animal research approved by the relevant IACUC or other animal research panel? NOTE: Any animal studies without IACUC approval will be automatically rejected.

Yes

Please indicate which methods were used in your research:

Diffusion MRI

Behavior

For human MRI, what field strength scanner do you use?

3.0T

Which processing packages did you use for your study?

Other, Please list - R package: glm, CMA

Provide references using APA citation style.

Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C. Y., Dennison, C. A., Hall, L. S., Lam, M., Watanabe, K., Frei, O., Ge, T., Harwood, J. C., Koopmans, F., Magnusson, S., Richards, A. L., Sidorenko, J., Wu, Y., … Schizophrenia Working Group of the Psychiatric Genomics Consortium (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604(7906), 502–508. https://doi.org/10.1038/s41586-022-04434-5
Stauffer, E. M., Bethlehem, R. A. I., Warrier, V., Murray, G. K., Romero-Garcia, R., Seidlitz, J., & Bullmore, E. T. (2021). Grey and white matter microstructure is associated with polygenic risk for schizophrenia. Molecular psychiatry, 26(12), 7709–7718. https://doi.org/10.1038/s41380-021-01260-5

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